Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

EGG Consortium

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight–blood pressure association is attributable to genetic effects, and not to intrauterine programming.

Original languageEnglish
Pages (from-to)804-814
Number of pages11
JournalNature Genetics
Volume51
Issue number5
DOIs
Publication statusPublished - 1 May 2019

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Birth Weight
Mothers
Blood Pressure
Alleles
Genome-Wide Association Study
Proxy
Random Allocation
Genotype
Parturition
Hypertension
Pressure
Health

Cite this

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title = "Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors",
abstract = "Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight–blood pressure association is attributable to genetic effects, and not to intrauterine programming.",
author = "Warrington, {Nicole M.} and Beaumont, {Robin N.} and Momoko Horikoshi and Day, {Felix R.} and {\O}yvind Helgeland and Charles Laurin and Jonas Bacelis and Shouneng Peng and Ke Hao and Bjarke Feenstra and Wood, {Andrew R.} and Anubha Mahajan and Jessica Tyrrell and Robertson, {Neil R.} and Rayner, {N. William} and Zhen Qiao and Moen, {Gunn Helen} and Marc Vaudel and Marsit, {Carmen J.} and Jia Chen and Michael Nodzenski and Schnurr, {Theresia M.} and Zafarmand, {Mohammad H.} and Bradfield, {Jonathan P.} and Niels Grarup and Kooijman, {Marjolein N.} and Ruifang Li-Gao and Frank Geller and Ahluwalia, {Tarunveer S.} and Lavinia Paternoster and Rico Rueedi and Ville Huikari and Hottenga, {Jouke Jan} and Lyytik{\"a}inen, {Leo Pekka} and Alana Cavadino and Sarah Metrustry and Cousminer, {Diana L.} and Ying Wu and Elisabeth Thiering and Wang, {Carol A.} and Have, {Christian T.} and Natalia Vilor-Tejedor and Joshi, {Peter K.} and Painter, {Jodie N.} and Ioanna Ntalla and Ronny Myhre and Niina Pitk{\"a}nen and {van Leeuwen}, {Elisabeth M.} and Raimo Joro and Vasiliki Lagou and Richmond, {Rebecca C.} and Ana Espinosa and Barton, {Sheila J.} and Inskip, {Hazel M.} and Holloway, {John W.} and Loreto Santa-Marina and Xavier Estivill and Wei Ang and Marsh, {Julie A.} and Christoph Reichetzeder and Letizia Marullo and Berthold Hocher and Lunetta, {Kathryn L.} and Murabito, {Joanne M.} and Relton, {Caroline L.} and Manolis Kogevinas and Leda Chatzi and Catherine Allard and Luigi Bouchard and Hivert, {Marie France} and Ge Zhang and Muglia, {Louis J.} and Jani Heikkinen and Morgen, {Camilla S.} and {van Kampen}, {Antoine H.C.} and {van Schaik}, {Barbera D.C.} and Mentch, {Frank D.} and Claudia Langenberg and Jian’an Luan and Scott, {Robert A.} and Zhao, {Jing Hua} and Gibran Hemani and Ring, {Susan M.} and Bennett, {Amanda J.} and Gaulton, {Kyle J.} and Juan Fernandez-Tajes and {van Zuydam}, {Natalie R.} and Carolina Medina-Gomez and {de Haan}, {Hugoline G.} and Rosendaal, {Frits R.} and Zolt{\'a}n Kutalik and Pedro Marques-Vidal and Shikta Das and Gonneke Willemsen and Hamdi Mbarek and Martina M{\"u}ller-Nurasyid and Marie Standl and Appel, {Emil V.R.} and Fonvig, {Cilius E.} and Caecilie Trier and {van Beijsterveldt}, {Catharina E.M.} and Mario Murcia and Mariona Bustamante and S{\'i}lvia Bonas-Guarch and Hougaard, {David M.} and Mercader, {Josep M.} and Allan Linneberg and Schraut, {Katharina E.} and Lind, {Penelope A.} and Medland, {Sarah E.} and Shields, {Beverley M.} and Knight, {Bridget A.} and Chai, {Jin Fang} and Kalliope Panoutsopoulou and Meike Bartels and Friman S{\'a}nchez and Jakob Stokholm and David Torrents and Vinding, {Rebecca K.} and Willems, {Sara M.} and Mustafa Atalay and Chawes, {Bo L.} and Peter Kovacs and Inga Prokopenko and Tuke, {Marcus A.} and Hanieh Yaghootkar and Ruth, {Katherine S.} and Jones, {Samuel E.} and Loh, {Po Ru} and Anna Murray and Weedon, {Michael N.} and Anke T{\"o}njes and Michael Stumvoll and Michaelsen, {Kim F.} and Eloranta, {Aino Maija} and Lakka, {Timo A.} and {van Duijn}, {Cornelia M.} and Wieland Kiess and Antje K{\"o}rner and Harri Niinikoski and Katja Pahkala and Raitakari, {Olli T.} and Bo Jacobsson and Eleftheria Zeggini and Dedoussis, {George V.} and Teo, {Yik Ying} and Saw, {Seang Mei} and Montgomery, {Grant W.} and Harry Campbell and Wilson, {James F.} and Vrijkotte, {Tanja G.M.} and Martine Vrijheid and {de Geus}, {Eco J.C.N.} and Hayes, {M. Geoffrey} and Kadarmideen, {Haja N.} and Holm, {Jens Christian} and Beilin, {Lawrence J.} and Pennell, {Craig E.} and Joachim Heinrich and Adair, {Linda S.} and Borja, {Judith B.} and Mohlke, {Karen L.} and Eriksson, {Johan G.} and Wid{\'e}n, {Elisabeth E.} and Hattersley, {Andrew T.} and Spector, {Tim D.} and Mika K{\"a}h{\"o}nen and Viikari, {Jorma S.} and Terho Lehtim{\"a}ki and Boomsma, {Dorret I.} and Sylvain Sebert and Peter Vollenweider and S{\o}rensen, {Thorkild I.A.} and Hans Bisgaard and Klaus B{\o}nnelykke and Murray, {Jeffrey C.} and Mads Melbye and Nohr, {Ellen A.} and Mook-Kanamori, {Dennis O.} and Fernando Rivadeneira and Albert Hofman and Felix, {Janine F.} and Jaddoe, {Vincent W.V.} and Torben Hansen and Charlotta Pisinger and Vaag, {Allan A.} and Oluf Pedersen and Uitterlinden, {Andr{\'e} G.} and J{\"a}rvelin, {Marjo Riitta} and Christine Power and Elina Hypp{\"o}nen and Scholtens, {Denise M.} and Lowe, {William L.} and {Davey Smith}, George and Timpson, {Nicholas J.} and Morris, {Andrew P.} and Wareham, {Nicholas J.} and Hakon Hakonarson and Grant, {Struan F.A.} and Frayling, {Timothy M.} and Lawlor, {Debbie A.} and Nj{\o}lstad, {P{\aa}l R.} and Stefan Johansson and Ong, {Ken K.} and McCarthy, {Mark I.} and Perry, {John R.B.} and Evans, {David M.} and Freathy, {Rachel M.} and {EGG Consortium}",
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month = "5",
day = "1",
doi = "10.1038/s41588-019-0403-1",
language = "English",
volume = "51",
pages = "804--814",
journal = "Nature Genetics",
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}

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. / EGG Consortium.

In: Nature Genetics, Vol. 51, No. 5, 01.05.2019, p. 804-814.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

AU - Warrington, Nicole M.

AU - Beaumont, Robin N.

AU - Horikoshi, Momoko

AU - Day, Felix R.

AU - Helgeland, Øyvind

AU - Laurin, Charles

AU - Bacelis, Jonas

AU - Peng, Shouneng

AU - Hao, Ke

AU - Feenstra, Bjarke

AU - Wood, Andrew R.

AU - Mahajan, Anubha

AU - Tyrrell, Jessica

AU - Robertson, Neil R.

AU - Rayner, N. William

AU - Qiao, Zhen

AU - Moen, Gunn Helen

AU - Vaudel, Marc

AU - Marsit, Carmen J.

AU - Chen, Jia

AU - Nodzenski, Michael

AU - Schnurr, Theresia M.

AU - Zafarmand, Mohammad H.

AU - Bradfield, Jonathan P.

AU - Grarup, Niels

AU - Kooijman, Marjolein N.

AU - Li-Gao, Ruifang

AU - Geller, Frank

AU - Ahluwalia, Tarunveer S.

AU - Paternoster, Lavinia

AU - Rueedi, Rico

AU - Huikari, Ville

AU - Hottenga, Jouke Jan

AU - Lyytikäinen, Leo Pekka

AU - Cavadino, Alana

AU - Metrustry, Sarah

AU - Cousminer, Diana L.

AU - Wu, Ying

AU - Thiering, Elisabeth

AU - Wang, Carol A.

AU - Have, Christian T.

AU - Vilor-Tejedor, Natalia

AU - Joshi, Peter K.

AU - Painter, Jodie N.

AU - Ntalla, Ioanna

AU - Myhre, Ronny

AU - Pitkänen, Niina

AU - van Leeuwen, Elisabeth M.

AU - Joro, Raimo

AU - Lagou, Vasiliki

AU - Richmond, Rebecca C.

AU - Espinosa, Ana

AU - Barton, Sheila J.

AU - Inskip, Hazel M.

AU - Holloway, John W.

AU - Santa-Marina, Loreto

AU - Estivill, Xavier

AU - Ang, Wei

AU - Marsh, Julie A.

AU - Reichetzeder, Christoph

AU - Marullo, Letizia

AU - Hocher, Berthold

AU - Lunetta, Kathryn L.

AU - Murabito, Joanne M.

AU - Relton, Caroline L.

AU - Kogevinas, Manolis

AU - Chatzi, Leda

AU - Allard, Catherine

AU - Bouchard, Luigi

AU - Hivert, Marie France

AU - Zhang, Ge

AU - Muglia, Louis J.

AU - Heikkinen, Jani

AU - Morgen, Camilla S.

AU - van Kampen, Antoine H.C.

AU - van Schaik, Barbera D.C.

AU - Mentch, Frank D.

AU - Langenberg, Claudia

AU - Luan, Jian’an

AU - Scott, Robert A.

AU - Zhao, Jing Hua

AU - Hemani, Gibran

AU - Ring, Susan M.

AU - Bennett, Amanda J.

AU - Gaulton, Kyle J.

AU - Fernandez-Tajes, Juan

AU - van Zuydam, Natalie R.

AU - Medina-Gomez, Carolina

AU - de Haan, Hugoline G.

AU - Rosendaal, Frits R.

AU - Kutalik, Zoltán

AU - Marques-Vidal, Pedro

AU - Das, Shikta

AU - Willemsen, Gonneke

AU - Mbarek, Hamdi

AU - Müller-Nurasyid, Martina

AU - Standl, Marie

AU - Appel, Emil V.R.

AU - Fonvig, Cilius E.

AU - Trier, Caecilie

AU - van Beijsterveldt, Catharina E.M.

AU - Murcia, Mario

AU - Bustamante, Mariona

AU - Bonas-Guarch, Sílvia

AU - Hougaard, David M.

AU - Mercader, Josep M.

AU - Linneberg, Allan

AU - Schraut, Katharina E.

AU - Lind, Penelope A.

AU - Medland, Sarah E.

AU - Shields, Beverley M.

AU - Knight, Bridget A.

AU - Chai, Jin Fang

AU - Panoutsopoulou, Kalliope

AU - Bartels, Meike

AU - Sánchez, Friman

AU - Stokholm, Jakob

AU - Torrents, David

AU - Vinding, Rebecca K.

AU - Willems, Sara M.

AU - Atalay, Mustafa

AU - Chawes, Bo L.

AU - Kovacs, Peter

AU - Prokopenko, Inga

AU - Tuke, Marcus A.

AU - Yaghootkar, Hanieh

AU - Ruth, Katherine S.

AU - Jones, Samuel E.

AU - Loh, Po Ru

AU - Murray, Anna

AU - Weedon, Michael N.

AU - Tönjes, Anke

AU - Stumvoll, Michael

AU - Michaelsen, Kim F.

AU - Eloranta, Aino Maija

AU - Lakka, Timo A.

AU - van Duijn, Cornelia M.

AU - Kiess, Wieland

AU - Körner, Antje

AU - Niinikoski, Harri

AU - Pahkala, Katja

AU - Raitakari, Olli T.

AU - Jacobsson, Bo

AU - Zeggini, Eleftheria

AU - Dedoussis, George V.

AU - Teo, Yik Ying

AU - Saw, Seang Mei

AU - Montgomery, Grant W.

AU - Campbell, Harry

AU - Wilson, James F.

AU - Vrijkotte, Tanja G.M.

AU - Vrijheid, Martine

AU - de Geus, Eco J.C.N.

AU - Hayes, M. Geoffrey

AU - Kadarmideen, Haja N.

AU - Holm, Jens Christian

AU - Beilin, Lawrence J.

AU - Pennell, Craig E.

AU - Heinrich, Joachim

AU - Adair, Linda S.

AU - Borja, Judith B.

AU - Mohlke, Karen L.

AU - Eriksson, Johan G.

AU - Widén, Elisabeth E.

AU - Hattersley, Andrew T.

AU - Spector, Tim D.

AU - Kähönen, Mika

AU - Viikari, Jorma S.

AU - Lehtimäki, Terho

AU - Boomsma, Dorret I.

AU - Sebert, Sylvain

AU - Vollenweider, Peter

AU - Sørensen, Thorkild I.A.

AU - Bisgaard, Hans

AU - Bønnelykke, Klaus

AU - Murray, Jeffrey C.

AU - Melbye, Mads

AU - Nohr, Ellen A.

AU - Mook-Kanamori, Dennis O.

AU - Rivadeneira, Fernando

AU - Hofman, Albert

AU - Felix, Janine F.

AU - Jaddoe, Vincent W.V.

AU - Hansen, Torben

AU - Pisinger, Charlotta

AU - Vaag, Allan A.

AU - Pedersen, Oluf

AU - Uitterlinden, André G.

AU - Järvelin, Marjo Riitta

AU - Power, Christine

AU - Hyppönen, Elina

AU - Scholtens, Denise M.

AU - Lowe, William L.

AU - Davey Smith, George

AU - Timpson, Nicholas J.

AU - Morris, Andrew P.

AU - Wareham, Nicholas J.

AU - Hakonarson, Hakon

AU - Grant, Struan F.A.

AU - Frayling, Timothy M.

AU - Lawlor, Debbie A.

AU - Njølstad, Pål R.

AU - Johansson, Stefan

AU - Ong, Ken K.

AU - McCarthy, Mark I.

AU - Perry, John R.B.

AU - Evans, David M.

AU - Freathy, Rachel M.

AU - EGG Consortium

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight–blood pressure association is attributable to genetic effects, and not to intrauterine programming.

AB - Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight–blood pressure association is attributable to genetic effects, and not to intrauterine programming.

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UR - http://www.scopus.com/inward/citedby.url?scp=85065213720&partnerID=8YFLogxK

U2 - 10.1038/s41588-019-0403-1

DO - 10.1038/s41588-019-0403-1

M3 - Article

VL - 51

SP - 804

EP - 814

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 5

ER -